There is an increasing recognition that the airways of persons with cystic fibrosis (CF) typically harbor complex polymicrobial communities that include numerous bacterial species. It is unknown, however, how changes in these communities relate to the progression of lung disease. More specifically, it is unclear how changes in the structure and/or activity of airway bacterial communities are associated with the intermittent pulmonary exacerbations that characterize CF. The long term objective of this project is to understand the microbiologic determinants of lung disease progression in CF in order to develop new strategies to improve the health of persons with CF. The specific aims of this project are to (i) characterize the airway microbial and inflammatory changes that occur with pulmonary exacerbations, (ii) develop a model that predicts the occurrence of pulmonary exacerbations based on monitoring airway microbial communities and inflammation, and (iii) develop a dynamic model of CF host-microbiome interactions that will provide information about the mechanisms involved in infection-driven lung disease in CF. We have prospectively collected thousands of daily sputum samples from people with CF, many of whom experienced an exacerbation during the sputum collection period. We will use next-generation DNA sequencing and analysis of bacterial metabolites to characterize the structure and activity of the bacterial communities in samples obtained around the time of pulmonary exacerbations. We are especially interested in samples that were obtained in the days or weeks immediately preceding exacerbation onset. Our study will identify microbial community changes that correlate with exacerbation onset, severity and recovery. This information has great potential to enable the development of better approaches to preventing or treating exacerbations in CF. In summary, the work performed in this project will result in basic discoveries about the causes of lung disease in CF, enable the translation of these discoveries into clinical practice, and foster training and mentoring of emerging scientists and physicians.